Various surgical and percutaneous therapies have been developed to reopen blocked channels, conduits, and other lumens, to remove diseased tissue, and to implant substitute tissue, or components thereof. While these therapies are effective, they often simultaneously injure cells or cellular components of the manipulated tissues.
The responses to injuries resulting from therapeutic interventions can cause complications that undo the beneficial effect of the intervention, or create new problems. For example, percutaneous transluminal angioplasty can open obstructed atherosclerotic arteries. However, the balloon-mediated stretch and crush injury to the arterial wall can lead to proliferation of the smooth muscle cells of the media of the artery, resulting in reclosure of the artery (“restenosis”) over the following months. This is observed in at least one-third of arteries treated. Another example is in the formation of adhesions after surgery, in which post-operative events result in the formation or proliferation of adventitious tissue that binds internal body surfaces together, causing discomfort, organ malfunction and potential morbidity and mortality. This can occur in many tissues and organs, including the intestine, the peritoneum, the heart, the pericardium, lungs, pleura, etc.
Various interventions have been proposed to minimize such problems. These include the use of stents and coatings in arteries (Slepian, in “Polymeric Endoluminal Paving” Cardiology Clinics 12(14) (November 1994), Slepian, et al, Circulation 88(4):part 2, 1-319 (1993), Hill-West, et al, Proc. Natl. Acad. Sci. USA 91:5967 (1994), U.S. Pat. No. 5,213,580, U.S. Pat. No. 5,800,538). In addition, the use of coatings, gels and fabrics can be used to prevent abdominal and pelvic adhesions (Hill-West et al, Obst. Gyne. 83:59 (1994)). Many of these treatments are administered after the injury has occurred, whether as a result of balloon angioplasty or otherwise, allowing the injured cells to initiate the series of processes involved in clotting, complement activation, and cellular response to release of cytokines, inducers of proliferation, and other biologically active molecules. It is difficult to stop these complex, interrelated processes once they have begun.
The present invention relates to methods, and compositions suitable for use therein, that minimize the reaction of cells and tissues, and of cells nearby or adjacent to them, to a subsequent injury.